This invention relates to control of ocular development and, more particularly, to the treatment of the eye to control the development of myopia (commonly known as nearsightedness).
It has been estimated that about one of every four persons on earth suffers from myopia. About one-half or more of these cases are axial myopia, i.e., an elongation of the eye along the visual axis.
At birth, the human eye is about two-thirds adult size and is even at that size relatively short in the axial direction. As a consequence, young children tend to be farsighted. During childhood, as the eye grows, there is a compensatory fine tuning of the optical properties of the cornea and lens to the increasing ocular length. Often the entire process is virtually perfect and no correction is needed for sharp vision at distance; the eye is emmetropic. When regulatory failure in this finely tuned process occurs, it usually goes toward a lengthened eye. As a result, distant images focus in front of the plane of the retina and axial myopia results. If, on the other hand, the regulatory failure leads to an eye whose ocular length is too short, near images focus behind the plane of the retina and the result is hyperopia (commonly known as farsightedness).
Over the years, many theories have been put forth to explain the development of myopia, e.g., inheritance, excessive near work, and environmental influences such as hours of sunshine, diet, etc. From these theories many preventative measures have been proposed including spectacles, eye exercise, eye rest, cycloplegia, and other drug therapies. The clinical literature on the subject is massive.
Based on a theory that substantial use of the eye by children for reading leads to the development of permanent nearsightedness or myopia, many remedies directed at the focussing mechanism at the front of the eye have been proposed. Largely these have been attempts either to block near focus through topical application of drugs or to remove any need for near focus through use of plus lenses that in effect perform the near focus task. Topical drugs that relax the focussing muscle of the eye, the ciliary muscle, are called cycloplegics and have been available for a century.
Some clinical studies have suggested that atropine, a long-acting cycloplegic, applied topically to the eye may retard development of myopia. Atropine treatment, however, is not practical: it causes dilation of the pupil, which results in light sensitivity, and its action to inhibit ocular focussing impairs near visual work like reading. In addition to the discomfort to the patient, there are indications that excess light can harm the retina and questions have been raised concerning the danger of the long-term use of atropine (or other strong cycloplegics) on the retina when exposed to bright light.
There is now substantial evidence to link the posterior part of the eye, specifically image quality at the retina and hence an extension of the nervous system, to the postnatal regulation of ocular growth. There is significant evidence of myopia resulting in an eye that is subjected to retinal image degradation. It has been shown that axial myopia can be experimentally induced, in either birds or primates, in an eye in which the retina is deprived of formed images, e.g., by suturing the eyelids or wearing an image-diffusing goggle. The experimental myopia induced in primates such as monkeys mimics the common axial myopia of humans.
Thus, the phenomenon of an animal's vision process apparently contributes to the feedback mechanism by which postnatal ocular growth is normally regulated and refractive error is determined. This indicates that this mechanism is neural and likely originates in the retina.
U.S. Pat. No. 5,055,302, to Laties and Stone, discloses a method of controlling the abnormal postnatal growth of the eye of a maturing animal using vasoactive intestinal peptide (VIP), PH1 or analogues of these peptides. These peptides were found to inhibit axial elongation of a myopic eye.
U.S. Pat. No. 5,122,522, to Laties and Stone, discloses a method of controlling the abnormal postnatal growth of the eye of a maturing animal using pirenzepine. Axial elongation of a myopic eye was inhibited upon application of pirenzepine.
Gamma aminobutyric acid, GABA, an amino acid present in the central nervous system, is also present in the eye. Mosinger et al., "GABA-like Immunoreactivity in the Vertebrate Retina: A Species Comparison", Exp. Eye Res. 42, 631-644 (1986). Gamma aminobutyric acid has two types of receptors: GABA.sub.A receptors and GABA.sub.B receptors. GABA.sub.A receptors preferentially bind the agonist muscimol and the antagonist bicuculline. GABA.sub.B receptors preferentially bind the agonist baclofen and the antagonist 2-OH saclofen. For purposes of this application, an agonist is an agent that activates a receptor, leading to an intracellular response. Thus, agonists mimic the effects of endogenous regulatory compounds. An antagonist, for the purposes of this discussion, is an agent that effectively inhibits the action of an agonist thereby inhibiting excessive or abnormal postnatal axial growth of the eye of a maturing animal. The antagonist is useful under conditions ordinarily leading to excessive or abnormal axial growth. GABA receptors are present in chick retina, see Fiszer De Plazas et al., "Light and Dark Adaptation Influences GABA Receptor Sites in the Chick Retina", Neurochemical Research, 11, 7, 973-981 (1986); as well as other vertebrate retinas.